1. Field of the Invention
This invention relates to the fields of radiochemistry, synthetic organic chemistry, and radiopharmaceuticals.
2. Description of the Related Art
Due to their electron-rich aromatic structure, nucleophilic (radio)fluorination of pyridines is challenging, especially at the meta position.
Few methods exist to produce 3- or 5-fluoro-substituted pyridines compatible with the constraints of 18F radiochemistry, which include the use of fluoride ions as the fluorine source and short reaction times1. Customary methods for the synthesis of 2- and 4-fluoropyridines such as substitution of halides, nitro, trimethyl ammonium salts2 or sulfonium salts3, work in very low yield for the 3- and 5-positions. Furthermore, these methods are limited to pyridines containing secondary strong electron withdrawing groups such as nitrile or carboxamide4-6. Pyridines that do not contain secondary electron withdrawing groups are amenable to fluorination through recently-developed methods such as the use of iodonium salts7,8 and iodonium ylides9. However, these methods often require precursors that are difficult to prepare.
Given the limited number of reactions yielding 3- and 5-fluoropyridines, there is a great need to develop new methods that are fast, react in high yield, and use readily available precursors.